(Nanowerk News) Cancer drugs that stimulate the immune system to attack tumors are a promising way to treat many types of cancer. However, some of these drugs produce too much systemic inflammation when given intravenously, making them dangerous to use in patients.
MIT researchers have now come up with a possible way around that hurdle. In a new study, they show that when immunostimulating prodrugs — inactive drugs that require activation in the body — are tuned for optimal activation times, they provoke the immune system to attack tumors without the side effects that occur when active forms of the drugs are suppressed. given.
The researchers designed the prodrug with a bottle brush-like structure based on a class of compounds called imidazoquinolines (IMDs). Mice treated with a bottle brush prodrug designed with optimized activation kinetics showed a significant reduction in tumor growth, without any side effects. The researchers hope that this approach could be used to enhance the immune system response in cancer patients, especially when combined with other immunotherapy drugs or cancer vaccines.
“Our library of bottlebrush prodrugs allowed us to demonstrate immunological effects in controlling the kinetics of immunotherapy, enabling us to enhance the immune response while minimizing side effects,” said Sachin Bhagchandani, an MIT graduate student who was the study’s lead author. “This kind of approach paves the way for scientists wishing to isolate the toxicity of some of the promising immunotherapeutic agents.”
Jeremiah Johnson, an MIT professor of chemistry, and Darrell Irvine, an Underwood-Prescott Professor with designations in the MIT department of Biological Engineering and Materials Science and Engineering, are senior authors of the paper, which appears in Science Advances (“The engineering kinetics of TLR7/8 agonist release from bottlebrush prodrugs enables tumor-focused stimulation of immunity”). Irvine is also an associate director of MIT’s Koch Institute for Integrative Cancer Research and a member of the Ragon Institutes of MGH, MIT, and Harvard.
Organic molecules known as IMD bind to cell receptors called Toll-like receptors that are found on macrophages and other cells of the innate immune system. When activated, these cells begin to produce cytokines and other inflammatory molecules.
In 1997, the FDA approved a topical IMD drug to treat several types of skin cancer. Since then, many other IMD drugs have been tested in clinical trials for various types of cancer, but none have been approved, in part because they produce too much systemic inflammation.
The MIT team set out to explore whether IMD prodrugs, which are deactivated until they are “activated” in the tumor microenvironment, could reduce these side effects. In recent years, the Johnson lab has developed a new type of platform prodrug that is shaped like a bottle brush. This nanoscale cylindrical structure consists of chains extending from a central backbone, giving the molecule a bottle brush-like structure. The inactive drugs are bound along the spine of the vial brush via a cleaved link that determines the release rate of the active IMD.
The researchers generated and compared six bottlebrush prodrugs that differ only by their degree of release, to investigate how the kinetics of prodrug activation impact antitumor responses. Using this prodrug bottlebrush, the researchers hope they can deliver active IMD to tumors while avoiding release into the bloodstream.
“Our ability to synthesize six bottlebrush prodrugs with uniquely identical sizes and shapes allowed us to isolate and study the kinetics of release as a key variable. Interestingly, we found that it is possible to identify prodrug structures that limit IMD exposure throughout the body, thereby avoiding toxicity, and activating tumors to confer antitumor efficacy,” said Johnson.
In preliminary studies on cells and mice, the researchers found that the prodrugs that activated the fastest did cause immune-related side effects, including weight loss and increased levels of cytokines. However, the moderate and slow release versions do not produce this effect.
The researchers then tested IMD’s bottlebrush prodrugs in two different mouse models of colon cancer. Because prodrugs are very small (about 10 nanometers), they can efficiently accumulate in tumors. Once there, they are picked up by innate immune cells, where their couplings are cleaved. The resulting active IMD release causes immune cells to release cytokines and other molecules that create a pro-inflammatory environment. This sequence of events activates nearby T cells to attack the tumor.
In both models, mice treated with the bottlebrush prodrug showed significantly slowed tumor growth. When the treatment was combined with checkpoint blockade inhibitors — another class of immunotherapy drugs — the tumors were completely eliminated in about 20 percent of the mice.
While mice treated with the IMD used in this study, known as resiquimod, showed reduced body weight, increased levels of cytokines, and decreased white blood cell counts, as expected, mice given the resiquimod vial brush prodrug did not show these effects.
“Our molecule can safely reduce this effect by controlling how much of the active drug is released in the blood,” says Bhagchandani. “If you minimize the release of active compounds there, then you can get an antitumor effect at the tumor site without systemic side effects.”
The findings suggest that the most promising use for IMD bottlebrush prodrugs is to administer them in combination with other drugs that stimulate an immune response. Another possibility is using IMD vial prodrugs as adjuvants to enhance the immune system’s response to cancer vaccines.
“The ability of the prodrug bottlebrush strategy to change where drugs accumulate in the body and when they are active is very exciting for safely activating an immune response against cancer or other diseases,” said Irvine.